Mysterious Protein-Folding Molecule Could Trigger Metabolic Disorders

The cell’s response to unfolded or misfolded proteins could be a cause, rather than a consequence, of metabolic disorders, report researchers at the Medical University of South Carolina (MUSC) in an article published online ahead of print on September 4, 2017 by Nature Structural & Molecular Biology. The researchers identified a little-known molecule as the trigger for this response.

There are links between protein-folding problems at the cellular level and a range of metabolic disorders, though it is unclear if those problems are causes or manifestations of such disorders. This study provides evidence that problems with protein folding contribute to certain metabolic disorders, according to Zihai Li, M.D., Ph.D., chair of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and principal investigator on the project. Feng Hong, M.D., Ph.D., in the Department of Microbiology and Immunology, is lead author on the paper.

The unfolded protein response in the cell plays important roles in aging and in many diseases, such as cancer, diabetes and neurodegenerative disease,” says Li. “Our study has uncovered a novel mechanism that triggers this response.”

When improperly folded molecules are encountered in cells, the unfolded protein response (UPR) is activated within the endoplasmic reticulum (ER). The ER is in charge of molecular quality control, making sure proteins, lipids and other molecules are folded properly before the cell attempts to use them for metabolic processes. Here, a master protein called grp78 is in contact with three main signaling hubs that make up the control center of the UPR. When an unfolded or misfolded protein is encountered by grp78, it breaks contact with those sensors and activates the UPR. The UPR then refolds or disposes of such molecules before they are shipped to the parts of the cell that need them.